Germ Cell Tumours: Difference between revisions

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*** '''Accounts for 1-2% of cancers among males in the United States'''

* '''Age'''

** '''Most common malignancy among males aged 20-40 years old'''

** '''Most common malignancy among males aged 20-39 years old[https://seer.cancer.gov/statistics-network/explorer/application.html]'''

=== Mortality ===

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** US 2021: 440[https://seer.cancer.gov/statfacts/html/testis.html]

*** 5-year relative survival: 94.9% (compared to prostate 97.5%, bladder 77.1%, and kidney/renal pelvis 75.6%)[https://seer.cancer.gov/statfacts/html/testis.html]

== Risk ~~factors~~ ==

== Risk Factors ==

* '''~~Established risk factors~~ (5):'''

* '''Inherited (3):'''

*# '''Cryptorchidism'''

*#* '''Ipsilateral testis: relative risk 4-6x; relative risk decreases to 2-3x if orchidopexy is performed before puberty'''

*#* '''Contralateral testis: slightly increased risk''' (relative risk 1.74x)

*# '''Family history of GCT'''

*# '''Personal history of GCT'''

*# '''Germ Cell Neoplasia In-Situ (GCNIS)'''

*# '''Germ Cell Neoplasia In-Situ (GCNIS)~~, previously~~ referred to as intratubular germ cell neoplasia (ITGCN) unclassified~~'''~~

*#* Previously referred to as intratubular germ cell neoplasia (ITGCN) unclassified

*#* '''All adult invasive GCTs arise from GCNIS, except spermatocytic seminoma.'''

*#*'''All adult invasive GCTs arise from GCNIS, except spermatocytic seminoma.'''

*#* Among males with GCNIS, the risk of developing invasive GCT is ≈50% at 5 years

*#* '''GCNIS develops before birth from an arrested gonocyte'''

*# '''Race'''

*#* '''Caucasian risk > African-American'''

*'''Acquired (2):'''

*#'''Cryptorchidism'''

*#* '''Ipsilateral testis: relative risk 4-6x; relative risk decreases to 2-3x if orchidopexy is performed before puberty'''

*#* '''Contralateral testis: slightly increased risk''' (relative risk 1.74x)

*#'''Personal history of GCT'''

== Genetics ==

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* '''Rapidly growing tumours'''

* '''Sites of metastasis'''

** '''Lymph nodes'''

*** '''Retroperitoneal lymph nodes'''

**** '''Most common site of metastasis'''

***** '''70-80% of GCT metastasis occurs by lymphatic spread''' from the primary tumor to the retroperitoneal lymph nodes and subsequently to distant sites.

****** '''Exception: choriocarcinoma, with a propensity for hematogenous dissemination.'''

*** '''Supraclavicular lymph nodes'''

*** '''Mediastinal lymph nodes'''

*** '''Inguinal lymph nodes in patients with previous scrotal violation'''

** '''Visceral'''

*** '''Lung'''

**** '''Second most common site of metastasis'''

**** '''Most common site of visceral metastases'''

****Pulmonary metastases of testicular GCT represents disease spread via the hematogenous route, whereas mediastinal and cervical metastases represent lymphatic spread.

**** '''Thoracic metastasis in the absence of retroperitoneal disease and/or elevated serum tumor markers is uncommon'''

*** '''Liver'''

=== Metastasis ===

==== Sites of metastasis ====

* '''Lymph nodes'''

** '''Retroperitoneal lymph nodes'''

*** '''Most common site of metastasis'''

**** '''70-80% of GCT metastasis occurs by lymphatic spread''' from the primary tumor to the retroperitoneal lymph nodes and subsequently to distant sites.

***** '''Exception: choriocarcinoma, with a propensity for hematogenous dissemination.'''

** '''Supraclavicular lymph nodes'''

** '''Mediastinal lymph nodes'''

** '''Inguinal lymph nodes in patients with previous scrotal violation'''

* '''Visceral'''

** '''Lung'''

*** '''Second most common site of metastasis'''

*** '''Most common site of visceral metastases'''

***Pulmonary metastases of testicular GCT represents disease spread via the hematogenous route, whereas mediastinal and cervical metastases represent lymphatic spread.

*** '''Thoracic metastasis in the absence of retroperitoneal disease and/or elevated serum tumor markers is uncommon'''

** '''Liver'''

*'''At the time of diagnosis, metastasis''' (regional or distant) '''is present in 33% of cases of NSGCT and 15% of cases of pure seminoma'''

== Diagnosis and Evaluation ==

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=== History and Physical Exam ===

* '''~~History~~'''

==== History ====

** '''Most common presentation of testicular cancer: painless scrotal mass'''

* '''Signs and Symptoms'''

** '''~~At the time~~ of ~~diagnosis, metastasis''' (regional or distant~~) '''~~is present in 33% of cases of NSGCT and 15% of cases of pure seminoma,''' and symptoms related to metastatic disease~~ are the presenting complaint in 10-20% of patients

**'''Most common presentation of testicular cancer: painless scrotal mass'''

* '''~~Physical exam~~'''

**'''Symptoms related to metastatic disease (e.g. shortness of breath)''' are the presenting complaint in 10-20% of patients

** '''Genitourinary'''

*** Palpate for any testicular or extra-testicular masses. Note relative size and consistency of affected and normal contralateral testicle.

==== Physical exam ====

****'''A firm intratesticular mass should be managed as a malignant neoplasm until proven otherwise and should be evaluated further with a scrotal ultrasound scan.'''

* '''Genitourinary'''

*** '''Differential diagnosis of a scrotal mass (7):'''

** Palpate for any testicular or extra-testicular masses. Note relative size and consistency of affected and normal contralateral testicle.

***# '''Testicular neoplasm'''

***'''A firm intratesticular mass should be managed as a malignant neoplasm until proven otherwise and should be evaluated further with a scrotal ultrasound scan.'''

***# '''~~Epididymoorchitis~~'''

** '''Differential diagnosis of a scrotal mass (8):'''

***# '''~~Torsion~~'''

**# '''Painless'''

***# '''~~Hematoma~~'''

**##'''Testicular neoplasm'''

***# '''~~Paratesticular neoplasm (benign or malignant)~~'''

**##'''Paratesticular neoplasm (benign or malignant)'''

***# '''~~Hernia~~'''

**## '''Hernia'''

***# '''~~Varicocele~~'''

**## '''Varicocele'''

***# '''~~Spermatocele~~'''

**## '''Spermatocele'''

** '''Sites of metastases'''

**#'''Painful'''

*** '''Supraclavicular lymph nodes'''

**##'''Torsion'''

*** Inguinal lymph nodes, if prior inguinal or scrotal surgery

**## '''Hematoma'''

** '''Gynecomastia'''

**## '''Epididymoorchitis'''

*** '''Occurs in 2% of males with GCT'''

* '''Sites of metastases'''

*** Results from elevated serum hCG levels, decreased androgen production, and/or increased estrogen levels

** '''Supraclavicular lymph nodes'''

** Inguinal lymph nodes, if prior inguinal or scrotal surgery

* '''Gynecomastia'''

** '''Occurs in 2% of males with GCT'''

** Results from elevated serum hCG levels, decreased androgen production, and/or increased estrogen levels

=== Labs ===

* '''Tumour markers (A YET, B SEC)~~'''~~

==== Tumour markers (A YET, B SEC) ====

** '''AFP~~'''~~

*** At diagnosis, elevated in 50-70% of low-stage (CS I, IIA, and IIB) NSGCT and 60-80% of advanced (CS IIC and III) NSGCT

===== AFP =====

*** '''Produced by (3):'''

* At diagnosis, elevated in 50-70% of low-stage (CS I, IIA, and IIB) NSGCT and 60-80% of advanced (CS IIC and III) NSGCT

***# '''Yolk sac'''

* '''Produced by (3):'''

***# '''EC'''

*# '''Yolk sac'''

***# '''Teratoma'''

*# '''EC'''

**** '''Choriocarcinomas and seminomas do not produce AFP'''

*# '''Teratoma'''

***** '''Clinical implication: pure seminoma in the primary tumor with an elevated serum AFP should be treated as NSGCT'''

** '''Choriocarcinomas and seminomas do not produce AFP'''

*** '''Upper limit < 11 ng/mL'''

*** '''Clinical implication: pure seminoma in the primary tumor with an elevated serum AFP should be treated as NSGCT'''

**** Despite most laboratories considering AFP > 8ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15-25 ng/mL in the absence of any pathology; '''treatment decisions based solely on “elevated” AFP levels that are stable and <25 ng/mL is discouraged'''

* '''Upper limit < 11 ng/mL'''

*** '''Serum half-life: 5-7 days'''

** Despite most laboratories considering AFP > 8ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15-25 ng/mL in the absence of any pathology; '''treatment decisions based solely on “elevated” AFP levels that are stable and <25 ng/mL is discouraged'''

*** '''Other causes of elevated AFP:'''

* '''Serum half-life: 5-7 days'''

***# '''Non-malignant liver disease (infectious, drug-induced, alcohol-induced, autoimmune)'''

* '''Other causes of elevated AFP:'''

***# '''Hepatocellular carcinoma'''

*# '''Non-malignant liver disease (infectious, drug-induced, alcohol-induced, autoimmune)'''

***# Cancers of the stomach, pancreas, biliary tract, and lung

*# '''Hepatocellular carcinoma'''

***# Ataxic telangiectasia

*# Cancers of the stomach, pancreas, biliary tract, and lung

***# Hereditary tyrosinemia

*# Ataxic telangiectasia

***# Hereditary persistence of AFP (a congenital alteration in the hepatic nuclear factor binding site of the AFP gene)

*# Hereditary tyrosinemia

** '''β-hCG~~'''~~

*# Hereditary persistence of AFP (a congenital alteration in the hepatic nuclear factor binding site of the AFP gene)

*** At diagnosis, elevated in 20-40% of low-stage NSGCT and 40-60% of advanced NSGCT

*** '''Produced by (3):'''

===== β-hCG =====

***# '''Seminoma (15% of cases)'''

* At diagnosis, elevated in 20-40% of low-stage NSGCT and 40-60% of advanced NSGCT

***# '''EC'''

* '''Produced by (3):'''

***# '''Choriocarcinoma'''

*# '''Seminoma (15% of cases)'''

*** '''Upper limit: <5 mU/mL'''

*# '''EC'''

****'''Levels > 10,000 IU/L are usually associated with choriocarcinoma.'''

*# '''Choriocarcinoma'''

*** '''Serum half-life: 24 to 36 hours''' (2019 AUA Update Peds Testis Tumours says 24-48 hours)

* '''Upper limit: <5 mU/mL'''

*** '''Other causes of elevated hCG:'''

**'''Levels > 10,000 IU/L are usually associated with choriocarcinoma.'''

***# '''Hypogonadism'''

* '''Serum half-life: 24 to 36 hours''' (2019 AUA Update Peds Testis Tumours says 24-48 hours)

***#* '''LH will be elevated and can be a cause false-positive elevated hCC due to cross-reactivity of the hCG assay with LH'''

* '''Other causes of elevated hCG:'''

***#** '''Supplemental testosterone decreases LH levels, allowing accurate assessment of hCG levels thereafter[https://pubmed.ncbi.nlm.nih.gov/88528/]'''

*# '''Hypogonadism'''

***# '''Cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder.'''

*#* '''LH will be elevated and can be a cause false-positive elevated hCC due to cross-reactivity of the hCG assay with LH'''

***#* The α subunit of hCG is common to several pituitary tumors, and so immunoassays for hCG are directed at the β subunit.

*#** '''Supplemental testosterone decreases LH levels, allowing accurate assessment of hCG levels thereafter[https://pubmed.ncbi.nlm.nih.gov/88528/]'''

***# '''Cannabis use'''

*# '''Cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder.'''

** '''LDH~~'''~~

*#* The α subunit of hCG is common to several pituitary tumors, and so immunoassays for hCG are directed at the β subunit.

*** At diagnosis, elevated in ≈20% of low-stage GCT and 20-60% of advanced GCT

*# '''Cannabis use'''

*** '''Least relevant and clinically applicable of the tumour markers'''

**** Non-specific marker

===== LDH =====

**** '''Main use in GCT is in the''' '''prognostic (S stage classification) assessment at diagnosis.'''

* At diagnosis, elevated in ≈20% of low-stage GCT and 20-60% of advanced GCT

**** '''Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.'''

* '''Least relevant and clinically applicable of the tumour markers'''

*** '''Normal value 48-115 IU/liter'''

** Non-specific marker

****Magnitude of LDH elevation correlates with bulk of disease.

** '''Main use in GCT is in the''' '''prognostic (S stage classification) assessment at diagnosis.'''

*** '''Serum half-life: ~~24 hours<~~/~~span>'''~~

** '''Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.'''

*** LDH is expressed in smooth, cardiac, and skeletal muscles and can be elevated from cancerous (kidney, lymphoma, GI, breast) or non-cancerous conditions (heart failure, anemia, HIV)

* '''Normal value 48-115 IU/liter'''

** '''Pre-orchiectomy tumour markers~~'''~~

**Magnitude of LDH elevation correlates with bulk of disease.

*** '''Uses (2):'''

* '''Serum half-life: varies[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947/]'''

***# '''Support initial diagnosis'''

* LDH is expressed in smooth, cardiac, and skeletal muscles and can be elevated from cancerous (kidney, lymphoma, GI, breast) or non-cancerous conditions (heart failure, anemia, HIV)

***#* '''Should not be used to guide decision making about whether or not to perform a radical orchiectomy''' ~~because~~ AFP or hCG levels in the normal range do not rule out GCT.

***# '''Interpret tumor marker levels after orchiectomy.'''

===== Pre-orchiectomy tumour markers =====

***#* '''Essential to know whether persistently elevated post-orchiectomy tumour markers are declining compared to pre-orchiectomy levels by their respective half-lives or not, or whether they are rising, as this impacts subsequent treatment decisions.'''

* '''Uses (2):'''

*** '''Should not be used for clinical staging and risk stratification'''

*# '''Support initial diagnosis'''

**** Can lead to over- or under-treatment with resulting excess rates of toxicity or relapse, respectively.

*#* '''Should not be used to guide decision making about whether or not to perform a radical orchiectomy'''

** '''Post-orchiectomy tumour markers~~'''~~

*#** AFP or hCG levels in the normal range do not rule out GCT

*** '''Uses (2):'''

*# '''Interpret tumor marker levels after orchiectomy'''

***# '''Evaluate for metastases in the case of persistently elevated/rising post-orchiectomy tumour markers'''

*#* '''Essential to know whether persistently elevated post-orchiectomy tumour markers are declining compared to pre-orchiectomy levels by their respective half-lives or not, or whether they are rising, as this impacts subsequent treatment decisions.'''

***#* ~~If borderline~~ elevated (within 3x upper limit of normal) post-orchiectomy markers (AFP and hCG), confirm a rising trend before management decisions are made as false-positive elevations may occur.

* '''Should not be used for clinical staging and risk stratification'''

***# '''Evaluate for recurrence during surveillance and after completion of therapy (chemotherapy, radiation, surgery).'''

** Can lead to over- or under-treatment with resulting excess rates of toxicity or relapse, respectively.

===== Post-orchiectomy tumour markers =====

* '''Uses (2):'''

*# '''Evaluate for metastases in the case of persistently elevated/rising post-orchiectomy tumour markers'''

*#* Tumour marker levels should normalize after 4 half-lives[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947]

*#**Serum AFP levels should return to normal levels 20–28 days after effective therapy.

*#*If borderline elevated (within 3x upper limit of normal) post-orchiectomy markers (AFP and hCG), confirm a rising trend before management decisions are made as false-positive elevations may occur.

*# '''Evaluate for recurrence during surveillance and after completion of therapy (chemotherapy, radiation, surgery).'''

=== Imaging ===

=== ~~Local~~ ===

=== Local ===

==== Modality ====

==== ~~'''~~Scrotal ultrasound with doppler~~'''~~ ====

===== Scrotal ultrasound with doppler =====

* '''Important to evaluate both testicles given''' '''2% incidence of bilateral GCT'''

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* '''Imaging findings'''

** '''Typical GCT is hypoechoic'''

** 2 or more discrete lesions may be identified

** 2 or more discrete lesions may be identified[[File:Ultrasound images of seminomas.jpg|none|thumb|493x493px|Source: [[commons:File:Ultrasound_images_of_seminomas.jpg|Wikipedia]] (a) Seminoma usually presents as a homogeneous hypoechoic nodule confined within the tunica albuginea. (b) Sonography shows a large heterogeneous mass occupying nearly the whole testis but still confined within the tunica albuginea, it is rare for seminoma to invade to peritesticular structures.]][[File:Ultrasonography of embryonal cell carcinoma.jpg|none|thumb|Embryonal cell carcinoma. Longitudinal ultrasound image of the testis shows an irregular heterogeneous mass that forms an irregular margin with the tunica albuginea. Source: [[wikipedia:Scrotal_ultrasound#/media/File:Ultrasonography_of_embryonal_cell_carcinoma.jpg|Wikipedia]]]]

** INSERT IMAGE

** '''Testicular microlithiasis'''

*** '''Unclear significance''' '''in the general population'''

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**** '''No further evaluation or screening in incidentally detected microlithiasis'''

**** '''If established risk factor and testicular microlithiasis, counsel patient about the potential increased risk of GCT, need for periodic self-examination and follow-up with a medical professional'''

*** insert image

[[File:Testicular microlithiasis 131206091733625.gif|thumb|Testicular microlithiasis in a patient with contralateral orchiectomy due to testicular malignancy. Echogenic foci viewed in testis as small white spots. Source: [[commons:File:Testicular_microlithiasis_131206091733625.gif|Wikipedia]]|center]]

==== ~~'''~~MRI~~'''~~ ====

===== MRI =====

* '''Can be considered an adjunct to scrotal ultrasound in patients with lesions suspicious for benign etiology'''

* '''Should not delay orchiectomy in patients in whom malignancy is suspected'''

=== ~~~~Metastasis~~~~ ===

=== Metastasis ===

* '''~~Regional~~'''

** Regional lymph nodes comprises (7):

==== Regional ====

**# Inter-aortocaval

* Regional lymph nodes comprises (7):

**# Para-aortic

*# Inter-aortocaval

**# Para-caval

*# Para-aortic

**# Pre-aortic

*# Para-caval

**# Pre-caval

*# Pre-aortic

**# Retro-aortic

*# Pre-caval

**# Retro-caval

*# Retro-aortic

** '''Modality'''

*# Retro-caval

*** '''CT abdomen/pelvis with oral and IV contrast'''

* '''Modality'''

**** '''Most effective imaging modality for regional staging'''

** '''CT abdomen/pelvis with oral and IV contrast'''

*** MRI

*** '''Most effective imaging modality for regional staging'''

**** Alternative to CT

** MRI

** '''Imaging findings'''

*** Alternative to CT

*** '''Retroperitoneal lymph nodes'''

* '''Imaging findings'''

**** '''Pattern of lymph drainage in the retroperitoneum is from right to left.'''

** '''Retroperitoneal lymph nodes'''

***** '''For right testis tumors, the primary drainage site is the inter-aortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.'''

*** '''Pattern of lymph drainage in the retroperitoneum is from right to left.'''

***** '''For left testis tumors, the primary drainage site is the para-aortic lymph nodes, followed by the inter-aortocaval nodes.'''

**** '''For right testis tumors, the primary drainage site is the inter-aortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.'''

**** [[File:Retroperitoneal lymph flow.jpg|thumb|Direction of lymphatic flow in the retroperitoneum]]

**** '''For left testis tumors, the primary drainage site is the para-aortic lymph nodes, followed by the inter-aortocaval nodes.'''

*** '''"Borderline" retroperitoneal lymph nodes'''

*** [[File:Retroperitoneal lymph flow.jpg|thumb|Direction of lymphatic flow in the retroperitoneum]]

**** '''Lymph nodes 5-9 mm in the primary landing zone should be viewed with suspicion for regional lymph node metastasis, particularly if they are anterior to the great vessels'''

** '''"Borderline" retroperitoneal lymph nodes'''

*** Limitations

*** '''Lymph nodes 5-9 mm in the primary landing zone should be viewed with suspicion for regional lymph node metastasis, particularly if they are anterior to the great vessels'''

**** Understaging

** '''Limitations'''

***** 25-35% of patients with CSI NSGCT and a “normal” CT scan will be found to have pathologically involved retroperitoneal lymph nodes at RPLND

*** '''Understaging'''

**** Overstaging

**** 25-35% of patients with CSI NSGCT and a “normal” CT scan will be found to have pathologically involved retroperitoneal lymph nodes at RPLND

***** 12-40% of patients with CS IIA and IIB disease will be found to have pathologically negative lymph nodes at RPLND

*** '''Overstaging'''

* '''Distant'''

**** 12-40% of patients with CS IIA and IIB disease will be found to have pathologically negative lymph nodes at RPLND

** '''Chest'''

*** '''Timing'''

**** '''Necessary to complete staging in patients with confirmed GCTs'''

**** '''Should not delay orchiectomy'''

*** '''Modality: plain-film chest x-ray vs. CT'''

**** '''Chest x-ray'''

***** '''Indications''' (AUA 2019 Guidelines)

****** '''Suspected clinical stage I seminoma'''; preferred over CT

******* '''When tumor markers are normal, the rate of skip metastasis to the thorax in seminoma is close to 0%,''' and the addition of CT chest to chest x-ray is very unlikely to alter treatment decisions.

**** '''CT scan'''

***** '''Indications (3)''' (AUA 2019 Guidelines)

*****# '''NSGCT'''

*****#* '''Skip metastases are more common in non-seminoma than seminoma.'''

*****# '''Elevated and rising post-orchiectomy markers (hCG and AFP)'''

*****# '''Any evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam.'''

** '''Other'''

*** '''Bone scan and CT brain'''

****'''No role for routine bone scintigraphy or brain CT imaging at the time of diagnosis.'''

***** In the absence of symptoms or other clinical indicators of disease, visceral metastasis to bone and brain is uncommon in GCT

***** '''Indications for bone scan and CT brain (3):'''

*****#'''Symptoms suggestive of central nervous system or bone involvement'''

*****# '''Poor prognosis disease.'''

*****#'''Highly elevated hCG (>10,000 mU/mL)'''

*****#*'''Highly elevated hCG are often associated with metastatic choriocarcinoma, which has a propensity for brain metastases.'''

*** '''FDG-PET'''

**** '''Currently, no role in the routine evaluation of NSGCT and seminoma at the time of diagnosis.'''

=== Timing ===

==== Distant ====

* '''~~Management~~ decisions ~~should be based~~ on imaging ~~studies performed within 4 weeks~~ of the ~~initiation~~ of ~~treatment~~''' ~~due to~~ the ~~rapid growth~~ of ~~GCTs~~.

* '''Chest'''

** '''Timing'''

*** '''Necessary to complete staging in patients with confirmed GCTs'''

*** '''Should not delay orchiectomy'''

** '''Modality: plain-film chest x-ray vs. CT'''

*** '''Chest x-ray'''

**** '''Indications[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''

***** '''Suspected clinical stage I seminoma'''; preferred over CT

****** '''When tumor markers are normal, the rate of skip metastasis to the thorax in seminoma is close to 0%,''' and the addition of CT chest to chest x-ray is very unlikely to alter treatment decisions.

*** '''CT scan'''

**** '''Indications (3)[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''

****# '''NSGCT'''

****#* '''Skip metastases are more common in non-seminoma than seminoma.'''

****# '''Elevated and rising post-orchiectomy markers (hCG and AFP)'''

****# '''Any evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam.'''

* '''Other'''

** '''Bone scan and CT brain'''

***'''No role for routine bone scintigraphy or brain CT imaging at the time of diagnosis.[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''

**** In the absence of symptoms or other clinical indicators of disease, visceral metastasis to bone and brain is uncommon in GCT

**** '''Indications for bone scan and CT brain (3):'''

****#'''Symptoms suggestive of central nervous system or bone involvement'''

****# '''Poor prognosis disease.'''

****#'''Highly elevated hCG (>10,000 mU/mL)'''

****#*'''Highly elevated hCG are often associated with metastatic choriocarcinoma, which has a propensity for brain metastases.'''

** '''FDG-PET'''

*** '''Currently, no role in the routine evaluation of NSGCT and seminoma at the time of diagnosis.'''

=== Other ===

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== Staging ==

* '''~~TNM~~''' '''~~(AJCC 8th edition§)~~'''

=== TNM (AJCC 8th edition§) ===

** '''~~T stage (primary tumor)~~'''

*** '''pTX''': cannot be assessed

==== T stage (primary tumor) ====

*** '''pT0''': no evidence of primary tumour

* '''pTX''': cannot be assessed

*** '''pTis''': germ cell neoplasia in situ

* '''pT0''': no evidence of primary tumour

*** '''pT1: tumour limited to testis (including rete testis invastion) without ~~lymphyovascular~~ invasion (LVI)'''

* '''pTis''': germ cell neoplasia in situ

**** '''For pure seminoma:'''

* '''pT1: tumour limited to testis (including rete testis invastion) without lymphovascular invasion (LVI)'''

***** '''pT1a: tumour size < 3 cm'''

** '''For pure seminoma:'''

***** '''pT1b: tumour size ≥ 3 cm'''

*** '''pT1a: tumour size < 3 cm'''

*** '''pT2: tumour limited to testis (including rete testis invastion) with LVI or tumour invading hilar soft tissue, epididymis or tunica vaginalis'''

*** '''pT1b: tumour size ≥ 3 cm'''

*** '''pT3: direct (continuous) spermatic cord soft tissue invasion'''

* '''pT2: tumour limited to testis (including rete testis invastion) with LVI or tumour invading hilar soft tissue, epididymis or tunica vaginalis'''

**** LVI of the spermatic cord without soft tissue invasion is not pT3

* '''pT3: direct (continuous) spermatic cord soft tissue invasion'''

*** '''pT4: direct scrotum invasion'''

** LVI of the spermatic cord without soft tissue invasion is not pT3

** '''~~N Stage (regional lymph node stage)~~'''

* '''pT4: direct scrotum invasion'''

*** '''Clinical'''

**** cNX: regional lymph nodes cannot be assessed

==== N Stage (regional lymph node stage) ====

**** cN0: no regional lymph node metastasis

* '''Clinical'''

**** '''cN1: metastasis with a lymph node mass ≤2 cm in greatest dimension OR multiple lymph nodes, each ≤2 cm cm in greatest dimension'''

** cNX: regional lymph nodes cannot be assessed

**** '''cN2: metastasis with a lymph node mass >2 cm but ≤5 cm in greatest dimension OR multiple lymph nodes, any one mass >2 cm but ≤5 cm'''

** cN0: no regional lymph node metastasis

**** '''cN3: metastasis with a lymph node mass >5 cm in greatest dimension'''

** '''cN1: metastasis with a lymph node mass ≤2 cm in greatest dimension OR multiple lymph nodes, each ≤2 cm cm in greatest dimension'''

*** '''Pathologic'''

** '''cN2: metastasis with a lymph node mass >2 cm but ≤5 cm in greatest dimension OR multiple lymph nodes, any one mass >2 cm but ≤5 cm'''

**** pNX''':''' regional lymph nodes cannot be assessed

** '''cN3: metastasis with a lymph node mass >5 cm in greatest dimension'''

**** pN0: no regional lymph node metastasis

* '''Pathologic'''

**** '''pN1:''' metastasis with a lymph node mass '''≤2 cm''' in greatest dimension '''AND ≤5 positive nodes''', none >2 cm in greatest dimension

** pNX''':''' regional lymph nodes cannot be assessed

**** '''pN2:'''

** pN0: no regional lymph node metastasis

***** Metastasis with a lymph node mass '''>2 cm but ≤5 cm''' in greatest dimension '''OR'''

** '''pN1:''' metastasis with a lymph node mass '''≤2 cm''' in greatest dimension '''AND ≤5 positive nodes''', none >2 cm in greatest dimension

***** '''>5 nodes positive,''' none >5 cm in greatest dimension OR

** '''pN2:'''

***** '''Extranodal extension of tumour'''

*** Metastasis with a lymph node mass '''>2 cm but ≤5 cm''' in greatest dimension '''OR'''

**** pN3: metastasis with a lymph node mass '''>5 cm''' in greatest dimension

*** '''>5 nodes positive,''' none >5 cm in greatest dimension OR

** '''Distant metastasis~~'''~~

*** '''Extranodal extension of tumour'''

*** MX: distant metastasis cannot be assessed

** pN3: metastasis with a lymph node mass '''>5 cm''' in greatest dimension

*** M0: no distant metastasis

*** '''M1a: non-regional lymph node (ex: iliac, inguinal, pelvic NOS) or lung metastasis'''

==== M stage (distant metastasis) ====

*** '''M1b: non-lung visceral metastasis'''

* MX: distant metastasis cannot be assessed

** '''Serum markers (S)~~'''~~

* M0: no distant metastasis

*** '''SX''': serum tumor markers not available or not performed

* '''M1a: non-regional lymph node (ex: iliac, inguinal, pelvic NOS) or lung metastasis'''

*** '''S0''': markers within normal limits

* '''M1b: non-lung visceral metastasis'''

*** '''S1: LDH < 1.5 x upper limit of normal, hCG < 5,000 mIU/mL and AFP < 1,000 ng/mL'''

*** '''S2: LDH 1.5 - 10 x upper limit of normal OR hCG 5,000 - 50,000 mIU/mL OR AFP 1,000 - 10,000 ng/mL'''

==== S stage (serum markers) ====

*** '''S3: LDH > 10 x upper limit of normal OR hCG > 50,000 mIU/mL OR AFP > 10,000 ng/mL'''

* '''SX''': serum tumor markers not available or not performed

* '''~~Clinical staging~~'''

* '''S0''': markers within normal limits

** '''Prognosis of GCT and initial management decisions are determined by clinical stage (CS)'''

* '''S1: LDH < 1.5 x upper limit of normal, hCG < 5,000 mIU/mL and AFP < 1,000 ng/mL'''

** '''Based on (3):'''

* '''S2: LDH 1.5 - 10 x upper limit of normal OR hCG 5,000 - 50,000 mIU/mL OR AFP 1,000 - 10,000 ng/mL'''

**# '''Pathologic stage of the primary tumour (pT stage)'''

* '''S3: LDH > 10 x upper limit of normal OR hCG > 50,000 mIU/mL OR AFP > 10,000 ng/mL'''

**# '''Presence and extent of regional (N stage) and distant metastatic disease (M stage)'''

**# '''Post-orchiectomy serum tumor marker levels (S stage)'''

=== Clinical staging ===

**#* Serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy to determine nadir for staging and risk stratification

* '''Prognosis of GCT and initial management decisions are determined by clinical stage (CS)'''

**#** For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment.

* '''Based on (3):'''

** '''Testicular cancer clinical stage groups'''

*# '''Pathologic stage of the primary tumour (pT stage)'''

*# '''Presence and extent of regional (N stage) and distant metastatic disease (M stage)'''

*# '''Post-orchiectomy serum tumor marker levels (S stage)'''

*#* Serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy to determine nadir for staging and risk stratification

*#** For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment.

* '''Testicular cancer clinical stage groups'''

{| class="wikitable"

Line 496:

Line 518:

*** Expert review of pathologic specimens should be considered in clinical scenarios where treatment decisions will be impacted.

**** Studies have shown that expert pathology review can change the pathological subtype in 1-4% of cases.[https://pubmed.ncbi.nlm.nih.gov/16045777/][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704081/]

* '''Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days.'''

* '''Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days.'''

** Due to the rapid ~~doubling time~~ of many GCT, particularly NSGCT, there is a risk of disease progression between staging studies and intervention. Therefore, risk adapted management decisions (i.e. RPLND for Stage IIA disease) should be made based on recent imaging and serum tumor marker levels to avoid undertreatment.

** Due to the rapid growth of many GCT, particularly NSGCT, there is a risk of disease progression between staging studies and intervention. Therefore, risk adapted management decisions (i.e. RPLND for Stage IIA disease) should be made based on recent imaging and serum tumor marker levels to avoid undertreatment.

* '''In patients with normal serum tumor markers (hCG and AFP) and equivocal imaging findings for metastasis, consider repeat imaging in 6-8 weeks to clarify the extent of disease prior to making a treatment recommendation'''.

* '''Prior to definitive management, patients should be counseled about the risks of (3):'''

Line 745:

Line 767:

*** '''CSIIB with lymph node >3cm: chemotherapy'''

* Routine surveillance CT imaging is unnecessary after complete resolution of disease.

*'''Surgery in Early Metastatic Seminoma (SEMS) Trial'''

**Study design: Phase II trial

**55 patients with pure testicular seminoma after radical orchiectomy with isolated retroperitoneal lymphadenopathy 1-3 cm in greatest dimension.

***No more than 2 lymph nodes could be enlarged radiographically and lymph nodes needed to be within the ipsilateral RPLND template

***Lymph node enlargement could be synchronous (stage IIA or IIB) or metachronous (stage I with recurrence).

***Open RPLND was performed by certified surgeons who performed ≥8 open RPLND surgeries in the year before site initiation or at least 25 open RPLND surgeries with the past 3 years

**Primary outcome: 2-year relapse-free survival

**Results

***Median follow-up after RPLND: 33 months

***In post-RPLND follow-up, one patient received a single cycle of carboplatin for pN2, all other patients were managed with surveillance

***Pathological nodal stage

****pN0: 16%

****pN1: 22%

****pN2: 56%

****pN3: 5%

***2-year relapse-free survival: 81% (86% cN1 vs. 64% cN2, p=0.04)

***2-year overall survival: 100%

**[https://pubmed.ncbi.nlm.nih.gov/36913642/ Daneshmand, Siamak, et al.] "Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy." ''Journal of Clinical Oncology'' (2023): JCO-22.

===== CSIIC and III seminoma =====

Line 753:

Line 793:

===== Special scenarios =====

~~====== Residual masses after radiotherapy for seminoma ======~~

* '''Patients should undergo biopsy and histologic confirmation of the suspected lesion before management decisions are made.'''

** '''Although rare, seminoma may transform into NSGCT elements, and this should be considered in patients with metastatic seminoma who fail to respond to conventional therapy.'''

** Either an open or a robotic/laparoscopic biopsy of the para-aortic mass is an acceptable approach if CT-guided biopsy is not feasible or the result is non-diagnostic.

** RPLND should not be performed without histologic confirmation of NSGCT pathology.

====== Residual masses after chemotherapy for seminoma ======

* '''After first-line chemotherapy, 60-80% of patients have radiologically detectable residual masses.'''

* After first-line chemotherapy, 60-80% of patients have radiologically detectable residual masses.

* '''Histology of residual masses:'''

** '''Necrosis 90%'''

Line 778:

Line 810:

** '''If residual masses< 3 cm: observation.'''

** Post-chemotherapy radiotherapy has no role in the management of residual masses

====== Residual masses after radiotherapy for seminoma ======

* '''Patients should undergo biopsy and histologic confirmation of the suspected lesion before management decisions are made.'''

** '''Although rare, seminoma may transform into NSGCT elements, and this should be considered in patients with metastatic seminoma who fail to respond to conventional therapy.'''

** Either an open or a robotic/laparoscopic biopsy of the para-aortic mass is an acceptable approach if CT-guided biopsy is not feasible or the result is non-diagnostic.

** RPLND should not be performed without histologic confirmation of NSGCT pathology.

====== Relapse of seminoma ======

Line 802:

Line 841:

** '''Guidelines''':

*** '''2010 CUA Consensus Statement: surveillance preferred for all CSI NSGCT'''

*** '''2019 AUA Guidelines:'''

*** '''2019 AUA Guidelines:'''

**** '''CSIA NSGCT: surveillance recommended'''

**** '''CSIA NSGCT: surveillance recommended'''

**** '''CSIB NSGCT: all options are recommended'''

**** '''CSIB NSGCT: all options are recommended'''

**** '''RPLND is recommended if there is any secondary somatic malignancy (e.g. rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor) in the primary tumor'''

* '''Surveillance for clinical stage I NSGCT'''

Line 947:

Line 986:

** '''Chemotherapy'''

*** '''Cisplatin is associated with fatigue, myelosuppression, infection, peripheral neuropathy, hearing loss, diminished renal function, and death.'''

***'''Etoposide is associated with myelosuppression'''

** '''Radiation'''

*** '''Associated fatigue, nausea and vomiting, leukopenia, and dyspepsia'''

Line 964:

Line 1,004:

*** Risk increased with either subdiaphragmatic radiation or platinum-based chemotherapy

*** Patients should establish regular care with a primary care physician for appropriate health care maintenance and cancer screening as appropriate.

** '''Chemotherapy specific'''

** '''Chemotherapy specific'''

*** '''Bleomycin ~~is associated with pulmonary~~ complications (including pulmonary fibrosis) ~~and~~ Raynaud phenomenon~~, but has only mild~~ myelosuppressive effects at high doses.'''

*** '''Bleomycin'''

*** '''Cisplatin ~~is associated with nephrotoxicity and neurotoxicity.~~'''

****'''Pulmonary complications (including pulmonary fibrosis)'''

*** '''~~Other long-term sequelae of chemotherapy include peripheral~~ neuropathy ~~and hearing~~ loss'''

****'''Raynaud phenomenon'''

****'''Mild myelosuppressive effects at high doses.'''

*** '''Cisplatin'''

****'''Nephrotoxicity'''

****'''Neurotoxicity'''

****'''Peripheral neuropathy'''

****'''Hearing loss'''

== Special scenarios ==

@@ Line 16: / Line 16: @@
 *** '''Accounts for 1-2% of cancers among males in the United States'''
 * '''Age'''
-** '''Most common malignancy among males aged 20-40 years old'''
+** '''Most common malignancy among males aged 20-39 years old[https://seer.cancer.gov/statistics-network/explorer/application.html]'''
 === Mortality ===
@@ Line 23: / Line 23: @@
 ** US 2021: 440[https://seer.cancer.gov/statfacts/html/testis.html]
 *** 5-year relative survival: 94.9% (compared to prostate 97.5%, bladder 77.1%, and kidney/renal pelvis 75.6%)[https://seer.cancer.gov/statfacts/html/testis.html]
-== Risk factors ==
+== Risk Factors ==
-* '''<span style="color:#ff0000">Established risk factors (5):</span>'''
+* '''<span style="color:#ff0000">Inherited (3):</span>'''
-*# '''<span style="color:#ff0000">Cryptorchidism</span>'''
-*#* '''Ipsilateral testis: relative risk 4-6x; relative risk decreases to 2-3x if orchidopexy is performed before puberty'''
-*#* '''Contralateral testis: slightly increased risk''' (relative risk 1.74x)
 *# '''<span style="color:#ff0000">Family history of GCT</span>'''
-*# '''<span style="color:#ff0000">Personal history of GCT</span>'''
+*# '''<span style="color:#ff0000">Germ Cell Neoplasia In-Situ (GCNIS)</span>'''
-*# '''<span style="color:#ff0000">Germ Cell Neoplasia In-Situ (GCNIS)</span>, previously referred to as intratubular germ cell neoplasia (ITGCN) unclassified'''
+*#* Previously referred to as intratubular germ cell neoplasia (ITGCN) unclassified
-*#* '''All adult invasive GCTs arise from GCNIS, except spermatocytic seminoma.'''
+*#*'''All adult invasive GCTs arise from GCNIS, except spermatocytic seminoma.'''
 *#* Among males with GCNIS, the risk of developing invasive GCT is ≈50% at 5 years
 *#* '''GCNIS develops before birth from an arrested gonocyte'''
 *# '''<span style="color:#ff0000">Race</span>'''
 *#* '''Caucasian risk > African-American'''
+*'''<span style="color:#ff0000">Acquired (2):</span>'''
+*#'''<span style="color:#ff0000">Cryptorchidism</span>'''
+*#* '''Ipsilateral testis: relative risk 4-6x; relative risk decreases to 2-3x if orchidopexy is performed before puberty'''
+*#* '''Contralateral testis: slightly increased risk''' (relative risk 1.74x)
+*#'''<span style="color:#ff0000">Personal history of GCT</span>'''
 == Genetics ==
@@ Line 86: / Line 88: @@
 * '''<span style="color:#ff0000">Rapidly growing tumours</span>'''
-* '''<span style="color:#ff0000">Sites of metastasis</span>'''
-** '''<span style="color:#ff0000">Lymph nodes</span>'''
-*** '''<span style="color:#ff0000">Retroperitoneal lymph nodes</span>'''
-**** '''<span style="color:#ff0000">Most common site of metastasis</span>'''
-***** '''70-80% of GCT metastasis occurs by lymphatic spread''' from the primary tumor to the retroperitoneal lymph nodes and subsequently to distant sites.
-****** '''Exception: choriocarcinoma, with a propensity for hematogenous dissemination.'''
-*** '''<span style="color:#ff0000">Supraclavicular lymph nodes</span>'''
-*** '''<span style="color:#ff0000">Mediastinal lymph nodes</span>'''
-*** '''<span style="color:#ff0000">Inguinal lymph nodes in patients with previous scrotal violation</span>'''
-** '''<span style="color:#ff0000">Visceral</span>'''
-*** '''<span style="color:#ff0000">Lung</span>'''
-**** '''<span style="color:#ff0000">Second most common site of metastasis</span>'''
-**** '''<span style="color:#ff0000">Most common site of visceral metastases</span>'''
-****Pulmonary metastases of testicular GCT represents disease spread via the hematogenous route, whereas mediastinal and cervical metastases represent lymphatic spread.
-**** '''Thoracic metastasis in the absence of retroperitoneal disease and/or elevated serum tumor markers is uncommon'''
-*** '''<span style="color:#ff0000">Liver</span>'''
+=== Metastasis ===
+==== <span style="color:#ff0000">Sites of metastasis</span> ====
+* '''<span style="color:#ff0000">Lymph nodes</span>'''
+** '''<span style="color:#ff0000">Retroperitoneal lymph nodes</span>'''
+*** '''<span style="color:#ff0000">Most common site of metastasis</span>'''
+**** '''70-80% of GCT metastasis occurs by lymphatic spread''' from the primary tumor to the retroperitoneal lymph nodes and subsequently to distant sites.
+***** '''Exception: choriocarcinoma, with a propensity for hematogenous dissemination.'''
+** '''<span style="color:#ff0000">Supraclavicular lymph nodes</span>'''
+** '''<span style="color:#ff0000">Mediastinal lymph nodes</span>'''
+** '''<span style="color:#ff0000">Inguinal lymph nodes in patients with previous scrotal violation</span>'''
+* '''<span style="color:#ff0000">Visceral</span>'''
+** '''<span style="color:#ff0000">Lung</span>'''
+*** '''<span style="color:#ff0000">Second most common site of metastasis</span>'''
+*** '''<span style="color:#ff0000">Most common site of visceral metastases</span>'''
+***Pulmonary metastases of testicular GCT represents disease spread via the hematogenous route, whereas mediastinal and cervical metastases represent lymphatic spread.
+*** '''Thoracic metastasis in the absence of retroperitoneal disease and/or elevated serum tumor markers is uncommon'''
+** '''<span style="color:#ff0000">Liver</span>'''
+*'''At the time of diagnosis, metastasis''' (regional or distant) '''is present in 33% of cases of NSGCT and 15% of cases of pure seminoma'''
 == Diagnosis and Evaluation ==
@@ Line 117: / Line 122: @@
 === History and Physical Exam ===
-* '''<span style="color:#ff0000">History</span>'''
+==== History ====
-** '''<span style="color:#ff0000">Most common presentation of testicular cancer: painless scrotal mass</span>'''
+* '''<span style="color:#ff0000">Signs and Symptoms</span>'''
-** '''At the time of diagnosis, metastasis''' (regional or distant) '''is present in 33% of cases of NSGCT and 15% of cases of pure seminoma,''' and symptoms related to metastatic disease are the presenting complaint in 10-20% of patients
+**'''<span style="color:#ff0000">Most common presentation of testicular cancer: painless scrotal mass</span>'''
-* '''<span style="color:#ff0000">Physical exam</span>'''
+**'''Symptoms related to metastatic disease (e.g. shortness of breath)''' are the presenting complaint in 10-20% of patients
-** '''Genitourinary'''
-*** Palpate for any testicular or extra-testicular masses. Note relative size and consistency of affected and normal contralateral testicle.
+==== Physical exam ====
-****'''A firm intratesticular mass should be managed as a malignant neoplasm until proven otherwise and should be evaluated further with a scrotal ultrasound scan.'''
+* '''Genitourinary'''
-*** '''<span style="color:#ff0000">Differential diagnosis of a scrotal mass (7):</span>'''
+** Palpate for any testicular or extra-testicular masses. Note relative size and consistency of affected and normal contralateral testicle.
-***# '''<span style="color:#ff0000">Testicular neoplasm</span>'''
+***'''A firm intratesticular mass should be managed as a malignant neoplasm until proven otherwise and should be evaluated further with a scrotal ultrasound scan.'''
-***# '''<span style="color:#ff0000">Epididymoorchitis</span>'''
+** '''<span style="color:#ff0000">Differential diagnosis of a scrotal mass (8):</span>'''
-***# '''<span style="color:#ff0000">Torsion</span>'''
+**# '''<span style="color:#ff0000">Painless</span>'''
-***# '''<span style="color:#ff0000">Hematoma</span>'''
+**##'''<span style="color:#ff0000">Testicular neoplasm</span>'''
-***# '''<span style="color:#ff0000">Paratesticular neoplasm (benign or malignant)</span>'''
+**##'''<span style="color:#ff0000">Paratesticular neoplasm (benign or malignant)</span>'''
-***# '''<span style="color:#ff0000">Hernia</span>'''
+**## '''<span style="color:#ff0000">Hernia</span>'''
-***# '''<span style="color:#ff0000">Varicocele</span>'''
+**## '''<span style="color:#ff0000">Varicocele</span>'''
-***# '''<span style="color:#ff0000">Spermatocele</span>'''
+**## '''<span style="color:#ff0000">Spermatocele</span>'''
-** '''Sites of metastases'''
+**#'''<span style="color:#ff0000">Painful</span>'''
-*** '''Supraclavicular lymph nodes'''
+**##'''<span style="color:#ff0000">Torsion</span>'''
-*** Inguinal lymph nodes, if prior inguinal or scrotal surgery
+**## '''<span style="color:#ff0000">Hematoma</span>'''
-** '''Gynecomastia'''
+**## '''<span style="color:#ff0000">Epididymoorchitis</span>'''
-*** '''Occurs in 2% of males with GCT'''
+* '''Sites of metastases'''
-*** Results from elevated serum hCG levels, decreased androgen production, and/or increased estrogen levels
+** '''Supraclavicular lymph nodes'''
+** Inguinal lymph nodes, if prior inguinal or scrotal surgery
+* '''Gynecomastia'''
+** '''Occurs in 2% of males with GCT'''
+** Results from elevated serum hCG levels, decreased androgen production, and/or increased estrogen levels
 === Labs ===
-* '''<span style="color:#ff0000">Tumour markers </span><span style="color:#0000ff">(A YET, B SEC)</span>'''
+==== <span style="color:#ff0000">Tumour markers </span><span style="color:#0000ff">(A YET, B SEC)</span> ====
-** '''<span style="color:#0000ff">A</span><span style="color:#ff0000">FP</span>'''
-*** At diagnosis, elevated in 50-70% of low-stage (CS I, IIA, and IIB) NSGCT and 60-80% of advanced (CS IIC and III) NSGCT
+===== <span style="color:#0000ff">A</span><span style="color:#ff0000">FP</span> =====
-*** '''<span style="color:#ff0000">Produced by (3):</span>'''
+* At diagnosis, elevated in 50-70% of low-stage (CS I, IIA, and IIB) NSGCT and 60-80% of advanced (CS IIC and III) NSGCT
-***# '''<span style="color:#0000ff">Y</span><span style="color:#ff0000">olk sac</span>'''
+* '''<span style="color:#ff0000">Produced by (3):</span>'''
-***# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
+*# '''<span style="color:#0000ff">Y</span><span style="color:#ff0000">olk sac</span>'''
-***# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">eratoma</span>'''
+*# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
-**** '''<span style="color:#ff0000">Choriocarcinomas and seminomas do not produce AFP</span>'''
+*# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">eratoma</span>'''
-***** '''<span style="color:#ff0000">Clinical implication: pure seminoma in the primary tumor with an elevated serum AFP should be treated as NSGCT</span>'''
+** '''<span style="color:#ff0000">Choriocarcinomas and seminomas do not produce AFP</span>'''
-*** '''Upper limit < 11 ng/mL'''
+*** '''<span style="color:#ff0000">Clinical implication: pure seminoma in the primary tumor with an elevated serum AFP should be treated as NSGCT</span>'''
-**** Despite most laboratories considering AFP > 8ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15-25 ng/mL in the absence of any pathology; '''treatment decisions based solely on “elevated” AFP levels that are stable and <25 ng/mL is discouraged'''
+* '''Upper limit < 11 ng/mL'''
-*** '''<span style="color:#ff0000">Serum half-life: 5-7 days</span>'''
+** Despite most laboratories considering AFP > 8ng/mL to be abnormally elevated, a proportion of the population may have levels up to 15-25 ng/mL in the absence of any pathology; '''treatment decisions based solely on “elevated” AFP levels that are stable and <25 ng/mL is discouraged'''
-*** '''Other causes of elevated AFP:'''
+* '''<span style="color:#ff0000">Serum half-life: 5-7 days</span>'''
-***# '''Non-malignant liver disease (infectious, drug-induced, alcohol-induced, autoimmune)'''
+* '''Other causes of elevated AFP:'''
-***# '''Hepatocellular carcinoma'''
+*# '''Non-malignant liver disease (infectious, drug-induced, alcohol-induced, autoimmune)'''
-***# Cancers of the stomach, pancreas, biliary tract, and lung
+*# '''Hepatocellular carcinoma'''
-***# Ataxic telangiectasia
+*# Cancers of the stomach, pancreas, biliary tract, and lung
-***# Hereditary tyrosinemia
+*# Ataxic telangiectasia
-***# Hereditary persistence of AFP (a congenital alteration in the hepatic nuclear factor binding site of the AFP gene)
+*# Hereditary tyrosinemia
-** '''<span style="color:#0000ff">β</span>-hCG'''
+*# Hereditary persistence of AFP (a congenital alteration in the hepatic nuclear factor binding site of the AFP gene)
-*** At diagnosis, elevated in 20-40% of low-stage NSGCT and 40-60% of advanced NSGCT
-*** '''<span style="color:#ff0000">Produced by (3):</span>'''
+===== <span style="color:#0000ff">β</span>-hCG =====
-***# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">eminoma (15% of cases)</span>'''
+* At diagnosis, elevated in 20-40% of low-stage NSGCT and 40-60% of advanced NSGCT
-***# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
+* '''<span style="color:#ff0000">Produced by (3):</span>'''
-***# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">horiocarcinoma</span>'''
+*# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">eminoma (15% of cases)</span>'''
-*** '''Upper limit: <5 mU/mL'''
+*# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">C</span>'''
-****'''<span style="color:#ff0000">Levels > 10,000 IU/L are usually associated with choriocarcinoma.</span>'''
+*# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">horiocarcinoma</span>'''
-*** '''<span style="color:#ff0000">Serum half-life: 24 to 36 hours</span>''' (2019 AUA Update Peds Testis Tumours says 24-48 hours)
+* '''Upper limit: <5 mU/mL'''
-*** '''<span style="color:#ff0000">Other causes of elevated hCG:</span>'''
+**'''<span style="color:#ff0000">Levels > 10,000 IU/L are usually associated with choriocarcinoma.</span>'''
-***# '''<span style="color:#ff0000">Hypogonadism</span>'''
+* '''<span style="color:#ff0000">Serum half-life: 24 to 36 hours</span>''' (2019 AUA Update Peds Testis Tumours says 24-48 hours)
-***#* '''<span style="color:#ff0000">LH will be elevated and can be a cause false-positive elevated hCC due to cross-reactivity of the hCG assay with LH</span>'''
+* '''<span style="color:#ff0000">Other causes of elevated hCG:</span>'''
-***#** '''<span style="color:#ff0000">Supplemental testosterone decreases LH levels, allowing accurate assessment of hCG levels thereafter[https://pubmed.ncbi.nlm.nih.gov/88528/]</span>'''
+*# '''<span style="color:#ff0000">Hypogonadism</span>'''
-***# '''Cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder.'''
+*#* '''<span style="color:#ff0000">LH will be elevated and can be a cause false-positive elevated hCC due to cross-reactivity of the hCG assay with LH</span>'''
-***#* The α subunit of hCG is common to several pituitary tumors, and so immunoassays for hCG are directed at the β subunit.
+*#** '''<span style="color:#ff0000">Supplemental testosterone decreases LH levels, allowing accurate assessment of hCG levels thereafter[https://pubmed.ncbi.nlm.nih.gov/88528/]</span>'''
-***# '''Cannabis use'''
+*# '''Cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder.'''
-** '''<span style="color:#ff0000">LDH</span>'''
+*#* The α subunit of hCG is common to several pituitary tumors, and so immunoassays for hCG are directed at the β subunit.
-*** At diagnosis, elevated in ≈20% of low-stage GCT and 20-60% of advanced GCT
+*# '''Cannabis use'''
-*** '''Least relevant and clinically applicable of the tumour markers'''
-**** Non-specific marker
+===== <span style="color:#ff0000">LDH</span> =====
-**** '''Main use in GCT is in the''' '''prognostic (S stage classification) assessment at diagnosis.'''
+* At diagnosis, elevated in ≈20% of low-stage GCT and 20-60% of advanced GCT
-**** '''Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.'''
+* '''Least relevant and clinically applicable of the tumour markers'''
-*** '''Normal value 48-115 IU/liter'''
+** Non-specific marker
-****Magnitude of LDH elevation correlates with bulk of disease.
+** '''Main use in GCT is in the''' '''prognostic (S stage classification) assessment at diagnosis.'''
-*** '''<span style="color:#ff0000">Serum half-life: 24 hours</span>'''
+** '''Treatment decisions based solely on LDH elevation in the setting of normal AFP and hCG should be discouraged.'''
-*** LDH is expressed in smooth, cardiac, and skeletal muscles and can be elevated from cancerous (kidney, lymphoma, GI, breast) or non-cancerous conditions (heart failure, anemia, HIV)
+* '''Normal value 48-115 IU/liter'''
-** '''<span style="color:#ff0000">Pre-orchiectomy tumour markers</span>'''
+**Magnitude of LDH elevation correlates with bulk of disease.
-*** '''<span style="color:#ff0000">Uses (2):</span>'''
+* '''<span style="color:#ff0000">Serum half-life: varies[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947/]</span>'''
-***# '''<span style="color:#ff0000">Support initial diagnosis</span>'''
+* LDH is expressed in smooth, cardiac, and skeletal muscles and can be elevated from cancerous (kidney, lymphoma, GI, breast) or non-cancerous conditions (heart failure, anemia, HIV)
-***#* '''<span style="color:#ff0000">Should not be used to guide decision making about whether or not to perform a radical orchiectomy''' because AFP or hCG levels in the normal range do not rule out GCT.
-***# '''<span style="color:#ff0000">Interpret tumor marker levels after orchiectomy.</span>'''
+===== <span style="color:#ff0000">Pre-orchiectomy tumour markers</span> =====
-***#* '''Essential to know whether persistently elevated post-orchiectomy tumour markers are declining compared to pre-orchiectomy levels by their respective half-lives or not, or whether they are rising, as this impacts subsequent treatment decisions.'''
+* '''<span style="color:#ff0000">Uses (2):</span>'''
-*** '''Should not be used for clinical staging and risk stratification'''
+*# '''<span style="color:#ff0000">Support initial diagnosis</span>'''
-**** Can lead to over- or under-treatment with resulting excess rates of toxicity or relapse, respectively.
+*#* '''<span style="color:#ff0000">Should not be used to guide decision making about whether or not to perform a radical orchiectomy'''
-** '''<span style="color:#ff0000">Post-orchiectomy tumour markers</span>'''
+*#** AFP or hCG levels in the normal range do not rule out GCT
-*** '''<span style="color:#ff0000">Uses (2):</span>'''
+*# '''<span style="color:#ff0000">Interpret tumor marker levels after orchiectomy</span>'''
-***# '''<span style="color:#ff0000">Evaluate for metastases in the case of persistently elevated/rising post-orchiectomy tumour markers</span>'''
+*#* '''Essential to know whether persistently elevated post-orchiectomy tumour markers are declining compared to pre-orchiectomy levels by their respective half-lives or not, or whether they are rising, as this impacts subsequent treatment decisions.'''
-***#* If borderline elevated (within 3x upper limit of normal) post-orchiectomy markers (AFP and hCG), confirm a rising trend before management decisions are made as false-positive elevations may occur.
+* '''Should not be used for clinical staging and risk stratification'''
-***# '''<span style="color:#ff0000">Evaluate for recurrence during surveillance and after completion of therapy (chemotherapy, radiation, surgery).</span>'''
+** Can lead to over- or under-treatment with resulting excess rates of toxicity or relapse, respectively.
+===== <span style="color:#ff0000">Post-orchiectomy tumour markers</span> =====
+* '''<span style="color:#ff0000">Uses (2):</span>'''
+*# '''<span style="color:#ff0000">Evaluate for metastases in the case of persistently elevated/rising post-orchiectomy tumour markers</span>'''
+*#* Tumour marker levels should normalize after 4 half-lives[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818947]
+*#**Serum AFP levels should return to normal levels 20–28 days after effective therapy.
+*#*If borderline elevated (within 3x upper limit of normal) post-orchiectomy markers (AFP and hCG), confirm a rising trend before management decisions are made as false-positive elevations may occur.
+*# '''<span style="color:#ff0000">Evaluate for recurrence during surveillance and after completion of therapy (chemotherapy, radiation, surgery).</span>'''
 === Imaging ===
-=== <span style="color:#ff0000">Local</span> ===
+=== Local ===
+==== Modality ====
-==== '''<span style="color:#ff0000">Scrotal ultrasound with doppler</span>''' ====
+===== Scrotal ultrasound with doppler =====
 * '''<span style="color:#ff0000">Important to evaluate both testicles given</span>''' '''<span style="color:#ff0000">2% incidence of bilateral GCT</span>'''
@@ Line 220: / Line 239: @@
 * '''Imaging findings'''
 ** '''Typical GCT is hypoechoic'''
-** 2 or more discrete lesions may be identified
+** 2 or more discrete lesions may be identified[[File:Ultrasound images of seminomas.jpg|none|thumb|493x493px|Source: [[commons:File:Ultrasound_images_of_seminomas.jpg|Wikipedia]] (a) Seminoma usually presents as a homogeneous hypoechoic nodule confined within the tunica albuginea. (b) Sonography shows a large heterogeneous mass occupying nearly the whole testis but still confined within the tunica albuginea, it is rare for seminoma to invade to peritesticular structures.]][[File:Ultrasonography of embryonal cell carcinoma.jpg|none|thumb|Embryonal cell carcinoma. Longitudinal ultrasound image of the testis shows an irregular heterogeneous mass that forms an irregular margin with the tunica albuginea. Source: [[wikipedia:Scrotal_ultrasound#/media/File:Ultrasonography_of_embryonal_cell_carcinoma.jpg|Wikipedia]]]]
-** INSERT IMAGE
 ** '''<span style="color:#ff0000">Testicular microlithiasis</span>'''
 *** '''Unclear significance''' '''in the general population'''
@@ Line 229: / Line 247: @@
 **** '''<span style="color:#ff0000">No further evaluation or screening in incidentally detected microlithiasis</span>'''
 **** '''<span style="color:#ff0000">If established risk factor and testicular microlithiasis, counsel patient about the potential increased risk of GCT, need for periodic self-examination and follow-up with a medical professional</span>'''
-*** insert image
+[[File:Testicular microlithiasis 131206091733625.gif|thumb|Testicular microlithiasis in a patient with contralateral orchiectomy due to testicular malignancy. Echogenic foci viewed in testis as small white spots. Source: [[commons:File:Testicular_microlithiasis_131206091733625.gif|Wikipedia]]|center]]
-==== '''<span style="color:#ff0000">MRI</span>''' ====
+===== MRI =====
 * '''<span style="color:#ff0000">Can be considered an adjunct to scrotal ultrasound in patients with lesions suspicious for benign etiology</span>'''
 * '''Should not delay orchiectomy in patients in whom malignancy is suspected'''
-=== <span style="color:#ff0000">Metastasis</span> ===
+=== Metastasis ===
-* '''<span style="color:#ff0000">Regional</span>'''
-** Regional lymph nodes comprises (7):
+==== Regional ====
-**# Inter-aortocaval
+* Regional lymph nodes comprises (7):
-**# Para-aortic
+*# Inter-aortocaval
-**# Para-caval
+*# Para-aortic
-**# Pre-aortic
+*# Para-caval
-**# Pre-caval
+*# Pre-aortic
-**# Retro-aortic
+*# Pre-caval
-**# Retro-caval
+*# Retro-aortic
-** '''<span style="color:#ff0000">Modality</span>'''
+*# Retro-caval
-*** '''<span style="color:#ff0000">CT abdomen/pelvis with oral and IV contrast</span>'''
+* '''<span style="color:#ff0000">Modality</span>'''
-**** '''<span style="color:#ff0000">Most effective imaging modality for regional staging</span>'''
+** '''<span style="color:#ff0000">CT abdomen/pelvis with oral and IV contrast</span>'''
-*** MRI
+*** '''<span style="color:#ff0000">Most effective imaging modality for regional staging</span>'''
-**** Alternative to CT
+** MRI
-** '''<span style="color:#ff0000">Imaging findings</span>'''
+*** Alternative to CT
-*** '''<span style="color:#ff0000">Retroperitoneal lymph nodes</span>'''
+* '''<span style="color:#ff0000">Imaging findings</span>'''
-**** '''<span style="color:#ff0000">Pattern of lymph drainage in the retroperitoneum is from right to left.</span>'''
+** '''<span style="color:#ff0000">Retroperitoneal lymph nodes</span>'''
-***** '''<span style="color:#ff0000">For right testis tumors, the primary drainage site is the inter-aortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.</span>'''
+*** '''<span style="color:#ff0000">Pattern of lymph drainage in the retroperitoneum is from right to left.</span>'''
-***** '''<span style="color:#ff0000">For left testis tumors, the primary drainage site is the para-aortic lymph nodes, followed by the inter-aortocaval nodes.</span>'''
+**** '''<span style="color:#ff0000">For right testis tumors, the primary drainage site is the inter-aortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.</span>'''
-**** [[File:Retroperitoneal lymph flow.jpg|thumb|Direction of lymphatic flow in the retroperitoneum]]
+**** '''<span style="color:#ff0000">For left testis tumors, the primary drainage site is the para-aortic lymph nodes, followed by the inter-aortocaval nodes.</span>'''
-*** '''<span style="color:#ff0000">"Borderline" retroperitoneal lymph nodes</span>'''
+*** [[File:Retroperitoneal lymph flow.jpg|thumb|Direction of lymphatic flow in the retroperitoneum]]
-**** '''<span style="color:#ff0000">Lymph nodes 5-9 mm in the primary landing zone should be viewed with suspicion for regional lymph node metastasis,</span> particularly if they are anterior to the great vessels'''
+** '''<span style="color:#ff0000">"Borderline" retroperitoneal lymph nodes</span>'''
-*** Limitations
+*** '''<span style="color:#ff0000">Lymph nodes 5-9 mm in the primary landing zone should be viewed with suspicion for regional lymph node metastasis,</span> particularly if they are anterior to the great vessels'''
-**** Understaging
+** '''Limitations'''
-***** 25-35% of patients with CSI NSGCT and a “normal” CT scan will be found to have pathologically involved retroperitoneal lymph nodes at RPLND
+*** '''Understaging'''
-**** Overstaging
+**** 25-35% of patients with CSI NSGCT and a “normal” CT scan will be found to have pathologically involved retroperitoneal lymph nodes at RPLND
-***** 12-40% of patients with CS IIA and IIB disease will be found to have pathologically negative lymph nodes at RPLND
+*** '''Overstaging'''
-* '''<span style="color:#ff0000">Distant</span>'''
+**** 12-40% of patients with CS IIA and IIB disease will be found to have pathologically negative lymph nodes at RPLND
-** '''<span style="color:#ff0000">Chest</span>'''
-*** '''<span style="color:#ff0000">Timing</span>'''
-**** '''<span style="color:#ff0000">Necessary to complete staging in patients with confirmed GCTs</span>'''
-**** '''<span style="color:#ff0000">Should not delay orchiectomy</span>'''
-*** '''Modality: plain-film chest x-ray vs. CT'''
-**** '''Chest x-ray'''
-***** '''Indications''' (AUA 2019 Guidelines)
-****** '''Suspected clinical stage I seminoma'''; preferred over CT
-******* '''When tumor markers are normal, the rate of skip metastasis to the thorax in seminoma is close to 0%,''' and the addition of CT chest to chest x-ray is very unlikely to alter treatment decisions.
-**** '''CT scan'''
-***** '''Indications (3)''' (AUA 2019 Guidelines)
-*****# '''NSGCT'''
-*****#* '''Skip metastases are more common in non-seminoma than seminoma.'''
-*****# '''Elevated and rising post-orchiectomy markers (hCG and AFP)'''
-*****# '''Any evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam.'''
-** '''Other'''
-*** '''Bone scan and CT brain'''
-****'''No role for routine bone scintigraphy or brain CT imaging at the time of diagnosis.'''
-***** In the absence of symptoms or other clinical indicators of disease, visceral metastasis to bone and brain is uncommon in GCT
-***** '''Indications for bone scan and CT brain (3):'''
-*****#'''Symptoms suggestive of central nervous system or bone involvement'''
-*****# '''Poor prognosis disease.'''
-*****#'''Highly elevated hCG (>10,000 mU/mL)'''
-*****#*'''<span style="color:#ff0000">Highly elevated hCG are often associated with metastatic choriocarcinoma, which has a propensity for brain metastases.</span>'''
-*** '''<span style="color:#ff0000">FDG-PET</span>'''
-**** '''<span style="color:#ff0000">Currently, no role in the routine evaluation of NSGCT and seminoma at the time of diagnosis.</span>'''
-=== Timing ===
+==== Distant ====
-* '''Management decisions should be based on imaging studies performed within 4 weeks of the initiation of treatment''' due to the rapid growth of GCTs.
+* '''<span style="color:#ff0000">Chest</span>'''
+** '''<span style="color:#ff0000">Timing</span>'''
+*** '''<span style="color:#ff0000">Necessary to complete staging in patients with confirmed GCTs</span>'''
+*** '''<span style="color:#ff0000">Should not delay orchiectomy</span>'''
+** '''<span style="color:#ff0000">Modality: plain-film chest x-ray vs. CT</span>'''
+*** '''<span style="color:#ff0000">Chest x-ray</span>'''
+**** '''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
+***** '''<span style="color:#ff0000">Suspected clinical stage I seminoma</span>'''; preferred over CT
+****** '''When tumor markers are normal, the rate of skip metastasis to the thorax in seminoma is close to 0%,''' and the addition of CT chest to chest x-ray is very unlikely to alter treatment decisions.
+*** '''<span style="color:#ff0000">CT scan</span>'''
+**** '''<span style="color:#ff0000">Indications (3)</span>[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
+****# '''<span style="color:#ff0000">NSGCT</span>'''
+****#* '''Skip metastases are more common in non-seminoma than seminoma.'''
+****# '''<span style="color:#ff0000">Elevated and rising post-orchiectomy markers (hCG and AFP)</span>'''
+****# '''<span style="color:#ff0000">Any evidence of metastases on abdominal/pelvic imaging, chest x-ray or physical exam.</span>'''
+* '''Other'''
+** '''Bone scan and CT brain'''
+***'''No role for routine bone scintigraphy or brain CT imaging at the time of diagnosis.[https://pubmed.ncbi.nlm.nih.gov/31059667/ ★]'''
+**** In the absence of symptoms or other clinical indicators of disease, visceral metastasis to bone and brain is uncommon in GCT
+**** '''Indications for bone scan and CT brain (3):'''
+****#'''Symptoms suggestive of central nervous system or bone involvement'''
+****# '''Poor prognosis disease.'''
+****#'''Highly elevated hCG (>10,000 mU/mL)'''
+****#*'''<span style="color:#ff0000">Highly elevated hCG are often associated with metastatic choriocarcinoma, which has a propensity for brain metastases.</span>'''
+** '''<span style="color:#ff0000">FDG-PET</span>'''
+*** '''<span style="color:#ff0000">Currently, no role in the routine evaluation of NSGCT and seminoma at the time of diagnosis.</span>'''
 === Other ===
@@ Line 311: / Line 328: @@
 == Staging ==
-* '''<span style="color:#ff0000">TNM</span>''' '''(AJCC 8th edition§)'''
+=== TNM (AJCC 8th edition§) ===
-** '''<span style="color:#ff0000">T stage (primary tumor)</span>'''
-*** '''pTX''': cannot be assessed
+==== T stage (primary tumor) ====
-*** '''pT0''': no evidence of primary tumour
+* '''pTX''': cannot be assessed
-*** '''pTis''': germ cell neoplasia in situ
+* '''pT0''': no evidence of primary tumour
-*** '''<span style="color:#ff0000">pT1: tumour limited to testis (including rete testis invastion) without lymphyovascular invasion (LVI)</span>'''
+* '''pTis''': germ cell neoplasia in situ
-**** '''<span style="color:#ff0000">For pure seminoma:</span>'''
+* '''<span style="color:#ff0000">pT1: tumour limited to testis (including rete testis invastion) without lymphovascular invasion (LVI)</span>'''
-***** '''<span style="color:#ff0000">pT1a: tumour size < 3 cm</span>'''
+** '''<span style="color:#ff0000">For pure seminoma:</span>'''
-***** '''<span style="color:#ff0000">pT1b: tumour size ≥ 3 cm</span>'''
+*** '''<span style="color:#ff0000">pT1a: tumour size < 3 cm</span>'''
-*** '''<span style="color:#ff0000">pT2: tumour limited to testis (including rete testis invastion) with LVI or tumour invading hilar soft tissue, epididymis or tunica vaginalis</span>'''
+*** '''<span style="color:#ff0000">pT1b: tumour size ≥ 3 cm</span>'''
-*** '''<span style="color:#ff0000">pT3: direct (continuous) spermatic cord soft tissue invasion</span>'''
+* '''<span style="color:#ff0000">pT2: tumour limited to testis (including rete testis invastion) with LVI or tumour invading hilar soft tissue, epididymis or tunica vaginalis</span>'''
-**** LVI of the spermatic cord without soft tissue invasion is not pT3
+* '''<span style="color:#ff0000">pT3: direct (continuous) spermatic cord soft tissue invasion</span>'''
-*** '''<span style="color:#ff0000">pT4: direct scrotum invasion</span>'''
+** LVI of the spermatic cord without soft tissue invasion is not pT3
-** '''<span style="color:#ff0000">N Stage (regional lymph node stage)</span>'''
+* '''<span style="color:#ff0000">pT4: direct scrotum invasion</span>'''
-*** '''<span style="color:#ff0000">Clinical</span>'''
-**** cNX: regional lymph nodes cannot be assessed
+==== N Stage (regional lymph node stage) ====
-**** cN0: no regional lymph node metastasis
+* '''<span style="color:#ff0000">Clinical</span>'''
-**** '''<span style="color:#ff0000">cN1: metastasis with a lymph node mass <u>≤2 cm</u> in greatest dimension OR multiple lymph nodes, each <u>≤2 cm</u> cm in greatest dimension</span>'''
+** cNX: regional lymph nodes cannot be assessed
-**** '''<span style="color:#ff0000">cN2: metastasis with a lymph node mass <u>>2 cm but ≤5</u> cm in greatest dimension OR multiple lymph nodes, any one mass >2 cm but ≤5 cm</span>'''
+** cN0: no regional lymph node metastasis
-**** '''<span style="color:#ff0000">cN3: metastasis with a lymph node mass <u>>5 cm</u> in greatest dimension'''</span>
+** '''<span style="color:#ff0000">cN1: metastasis with a lymph node mass <u>≤2 cm</u> in greatest dimension OR multiple lymph nodes, each <u>≤2 cm</u> cm in greatest dimension</span>'''
-*** '''Pathologic'''
+** '''<span style="color:#ff0000">cN2: metastasis with a lymph node mass <u>>2 cm but ≤5</u> cm in greatest dimension OR multiple lymph nodes, any one mass >2 cm but ≤5 cm</span>'''
-**** pNX''':''' regional lymph nodes cannot be assessed
+** '''<span style="color:#ff0000">cN3: metastasis with a lymph node mass <u>>5 cm</u> in greatest dimension'''</span>
-**** pN0: no regional lymph node metastasis
+* '''Pathologic'''
-**** '''pN1:''' metastasis with a lymph node mass '''≤2 cm''' in greatest dimension '''AND ≤5 positive nodes''', none >2 cm in greatest dimension
+** pNX''':''' regional lymph nodes cannot be assessed
-**** '''pN2:'''
+** pN0: no regional lymph node metastasis
-***** Metastasis with a lymph node mass '''>2 cm but ≤5 cm''' in greatest dimension '''OR'''
+** '''pN1:''' metastasis with a lymph node mass '''≤2 cm''' in greatest dimension '''AND ≤5 positive nodes''', none >2 cm in greatest dimension
-***** '''>5 nodes positive,''' none >5 cm in greatest dimension OR
+** '''pN2:'''
-***** '''Extranodal extension of tumour'''
+*** Metastasis with a lymph node mass '''>2 cm but ≤5 cm''' in greatest dimension '''OR'''
-**** pN3: metastasis with a lymph node mass '''>5 cm''' in greatest dimension
+*** '''>5 nodes positive,''' none >5 cm in greatest dimension OR
-** '''Distant metastasis'''
+*** '''Extranodal extension of tumour'''
-*** MX: distant metastasis cannot be assessed
+** pN3: metastasis with a lymph node mass '''>5 cm''' in greatest dimension
-*** M0: no distant metastasis
-*** '''M1a: non-regional lymph node (ex: iliac, inguinal, pelvic NOS) or lung metastasis'''
+==== M stage (distant metastasis) ====
-*** '''M1b: non-lung visceral metastasis'''
+* MX: distant metastasis cannot be assessed
-** '''Serum markers (S)'''
+* M0: no distant metastasis
-*** '''SX''': serum tumor markers not available or not performed
+* '''M1a: non-regional lymph node (ex: iliac, inguinal, pelvic NOS) or lung metastasis'''
-*** '''S0''': markers within normal limits
+* '''M1b: non-lung visceral metastasis'''
-*** '''S1: LDH < 1.5 x upper limit of normal, hCG < 5,000 mIU/mL and AFP < 1,000 ng/mL'''
-*** '''S2: LDH 1.5 - 10 x upper limit of normal OR hCG 5,000 - 50,000 mIU/mL OR AFP 1,000 - 10,000 ng/mL'''
+==== S stage (serum markers) ====
-*** '''S3: LDH > 10 x upper limit of normal OR hCG > 50,000 mIU/mL OR AFP > 10,000 ng/mL'''
+* '''SX''': serum tumor markers not available or not performed
-* '''<span style="color:#ff0000">Clinical staging'''
+* '''S0''': markers within normal limits
-** '''<span style="color:#ff0000">Prognosis of GCT and initial management decisions are determined by clinical stage (CS)'''
+* '''S1: LDH < 1.5 x upper limit of normal, hCG < 5,000 mIU/mL and AFP < 1,000 ng/mL'''
-** '''<span style="color:#ff0000">Based on (3):'''
+* '''S2: LDH 1.5 - 10 x upper limit of normal OR hCG 5,000 - 50,000 mIU/mL OR AFP 1,000 - 10,000 ng/mL'''
-**# '''<span style="color:#ff0000">Pathologic stage of the primary tumour (pT stage)'''
+* '''S3: LDH > 10 x upper limit of normal OR hCG > 50,000 mIU/mL OR AFP > 10,000 ng/mL'''
-**# '''<span style="color:#ff0000">Presence and extent of regional (N stage) and distant metastatic disease (M stage)'''
-**# '''<span style="color:#ff0000">Post-orchiectomy serum tumor marker levels (S stage)'''
+=== Clinical staging ===
-**#* Serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy to determine nadir for staging and risk stratification
+* '''<span style="color:#ff0000">Prognosis of GCT and initial management decisions are determined by clinical stage (CS)'''
-**#** For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment.
+* '''<span style="color:#ff0000">Based on (3):'''
-** '''Testicular cancer clinical stage groups'''
+*# '''<span style="color:#ff0000">Pathologic stage of the primary tumour (pT stage)'''
+*# '''<span style="color:#ff0000">Presence and extent of regional (N stage) and distant metastatic disease (M stage)'''
+*# '''<span style="color:#ff0000">Post-orchiectomy serum tumor marker levels (S stage)'''
+*#* Serum tumor markers (AFP, hCG, and LDH) should be repeated at appropriate T1/2 time intervals after orchiectomy to determine nadir for staging and risk stratification
+*#** For patients with elevated AFP or hCG post-orchiectomy, clinicians should monitor serum tumor markers to establish nadir levels before treatment only if marker nadir levels would influence treatment.
+* '''Testicular cancer clinical stage groups'''
 {| class="wikitable"
@@ Line 496: / Line 518: @@
 *** Expert review of pathologic specimens should be considered in clinical scenarios where treatment decisions will be impacted.
 **** Studies have shown that expert pathology review can change the pathological subtype in 1-4% of cases.[https://pubmed.ncbi.nlm.nih.gov/16045777/][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704081/]
-* '''Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days.'''
+* '''<span style="color:#ff0000">Management decisions should be based on imaging obtained within the preceding 4 weeks and serum tumor markers (hCG and AFP) within the preceding 10 days.</span>'''
-** Due to the rapid doubling time of many GCT, particularly NSGCT, there is a risk of disease progression between staging studies and intervention. Therefore, risk adapted management decisions (i.e. RPLND for Stage IIA disease) should be made based on recent imaging and serum tumor marker levels to avoid undertreatment.
+** Due to the rapid growth of many GCT, particularly NSGCT, there is a risk of disease progression between staging studies and intervention. Therefore, risk adapted management decisions (i.e. RPLND for Stage IIA disease) should be made based on recent imaging and serum tumor marker levels to avoid undertreatment.
 * '''In patients with normal serum tumor markers (hCG and AFP) and equivocal imaging findings for metastasis, consider repeat imaging in 6-8 weeks to clarify the extent of disease prior to making a treatment recommendation'''.
 * '''<span style="color:#ff0000">Prior to definitive management, patients should be counseled about the risks of (3):</span>'''
@@ Line 745: / Line 767: @@
 *** '''CSIIB with lymph node >3cm: chemotherapy'''
 * Routine surveillance CT imaging is unnecessary after complete resolution of disease.
+*'''<span style="color:#ff00ff">Surgery in Early Metastatic Seminoma (SEMS) Trial</span>'''
+**Study design: Phase II trial
+**55 patients with pure testicular seminoma after radical orchiectomy with isolated retroperitoneal lymphadenopathy 1-3 cm in greatest dimension.
+***No more than 2 lymph nodes could be enlarged radiographically and lymph nodes needed to be within the ipsilateral RPLND template
+***Lymph node enlargement could be synchronous (stage IIA or IIB) or metachronous (stage I with recurrence).
+***Open RPLND was performed by certified surgeons who performed ≥8 open RPLND surgeries in the year before site initiation or at least 25 open RPLND surgeries with the past 3 years
+**Primary outcome: 2-year relapse-free survival
+**Results
+***Median follow-up after RPLND: 33 months
+***In post-RPLND follow-up, one patient received a single cycle of carboplatin for pN2, all other patients were managed with surveillance
+***Pathological nodal stage
+****pN0: 16%
+****pN1: 22%
+****pN2: 56%
+****pN3: 5%
+***2-year relapse-free survival: 81% (86% cN1 vs. 64% cN2, p=0.04)
+***2-year overall survival: 100%
+**[https://pubmed.ncbi.nlm.nih.gov/36913642/ Daneshmand, Siamak, et al.] "Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy." ''Journal of Clinical Oncology'' (2023): JCO-22.
 ===== CSIIC and III seminoma =====
@@ Line 753: / Line 793: @@
 ===== Special scenarios =====
-====== Residual masses after radiotherapy for seminoma ======
-* '''Patients should undergo biopsy and histologic confirmation of the suspected lesion before management decisions are made.'''
-** '''Although rare, seminoma may transform into NSGCT elements, and this should be considered in patients with metastatic seminoma who fail to respond to conventional therapy.'''
-** Either an open or a robotic/laparoscopic biopsy of the para-aortic mass is an acceptable approach if CT-guided biopsy is not feasible or the result is non-diagnostic.
-** RPLND should not be performed without histologic confirmation of NSGCT pathology.
 ====== Residual masses after chemotherapy for seminoma ======
+* '''After first-line chemotherapy, 60-80% of patients have radiologically detectable residual masses.'''
-* After first-line chemotherapy, 60-80% of patients have radiologically detectable residual masses.
 * '''<span style="color:#ff0000">Histology of residual masses:</span>'''
 ** '''<span style="color:#ff0000">Necrosis 90%</span>'''
@@ Line 778: / Line 810: @@
 ** '''<span style="color:#ff0000">If residual masses< 3 cm: observation.</span>'''
 ** Post-chemotherapy radiotherapy has no role in the management of residual masses
+====== Residual masses after radiotherapy for seminoma ======
+* '''Patients should undergo biopsy and histologic confirmation of the suspected lesion before management decisions are made.'''
+** '''Although rare, seminoma may transform into NSGCT elements, and this should be considered in patients with metastatic seminoma who fail to respond to conventional therapy.'''
+** Either an open or a robotic/laparoscopic biopsy of the para-aortic mass is an acceptable approach if CT-guided biopsy is not feasible or the result is non-diagnostic.
+** RPLND should not be performed without histologic confirmation of NSGCT pathology.
 ====== Relapse of seminoma ======
@@ Line 802: / Line 841: @@
 ** '''Guidelines''':
 *** '''2010 CUA Consensus Statement: surveillance preferred for all CSI NSGCT'''
-*** '''2019 AUA Guidelines:'''
+*** '''<span style="color:#ff0000">2019 AUA Guidelines:</span>'''
-**** '''CSIA NSGCT: surveillance recommended'''
+**** '''<span style="color:#ff0000">CSIA NSGCT: surveillance recommended</span>'''
-**** '''CSIB NSGCT: all options are recommended'''
+**** '''<span style="color:#ff0000">CSIB NSGCT: all options are recommended</span>'''
 **** '''<span style="color:#ff0000">RPLND is recommended if there is any secondary somatic malignancy (e.g. rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor) in the primary tumor</span>'''
 * '''<span style="color:#ff0000">Surveillance for clinical stage I NSGCT</span>'''
@@ Line 947: / Line 986: @@
 ** '''Chemotherapy'''
 *** '''Cisplatin is associated with fatigue, myelosuppression, infection, peripheral neuropathy, hearing loss, diminished renal function, and death.'''
+***'''Etoposide is associated with myelosuppression'''
 ** '''Radiation'''
 *** '''Associated fatigue, nausea and vomiting, leukopenia, and dyspepsia'''
@@ Line 964: / Line 1,004: @@
 *** Risk increased with either subdiaphragmatic radiation or platinum-based chemotherapy
 *** Patients should establish regular care with a primary care physician for appropriate health care maintenance and cancer screening as appropriate.
-** '''Chemotherapy specific'''
+** '''<span style="color:#ff0000">Chemotherapy specific'''
-*** '''Bleomycin is associated with pulmonary complications (including pulmonary fibrosis) and Raynaud phenomenon, but has only mild myelosuppressive effects at high doses.'''
+*** '''<span style="color:#ff0000">Bleomycin'''
-*** '''Cisplatin is associated with nephrotoxicity and neurotoxicity.'''
+****'''<span style="color:#ff0000">Pulmonary complications (including pulmonary fibrosis)'''
-*** '''Other long-term sequelae of chemotherapy include peripheral neuropathy and hearing loss'''
+****'''<span style="color:#ff0000">Raynaud phenomenon'''
+****'''Mild myelosuppressive effects at high doses.'''
+*** '''<span style="color:#ff0000">Cisplatin'''
+****'''<span style="color:#ff0000">Nephrotoxicity'''
+****'''<span style="color:#ff0000">Neurotoxicity'''
+****'''<span style="color:#ff0000">Peripheral neuropathy'''
+****'''<span style="color:#ff0000">Hearing loss'''
 == Special scenarios ==